Modulation of Radiation Biomarkers in a Randomized Phase II Study of 131I-MIBG With or Without Radiation Sensitizers for Relapsed or Refractory Neuroblastoma

Purpose: I-131-metaiodobenzylguanidine (I-131-MIBG) has demonstrated efficacy as a single agent in neuroblastoma. Recent trials have focused on I-131-MIBG combination strategies, though little is known about the effect of putative radiosensitizers on biological markers of radiation exposure. Methods and Materials: NANT2011-01 evaluated I-131-MIBG therapy alone (arm A) or in combination with vincristine/irinotecan (arm B) or vorinostat (arm C) for patients with relapsed or refractory neuroblastoma. Blood samples were collected before and after I-131-MIBG infusion to determine levels of radiation-associated biomarkers (transcript and protein). The association of biomarker with treatment arm, clinical response, and treatment toxicity was analyzed. Results: The cohort included 99 patients who had at least 1 biomarker available for analysis. Significant modulation in most biomarkers between baseline, 72, and 96 hours following I-131-MIBG was observed. Patients in arm C had the lowest degree of modulation in FLT3 ligand protein. Lower baseline BCL2 transcript levels were associated with higher overall response. Patients with greater increases in FLT3 ligand at 96 hours after I-131-MIBG therapy were significantly more likely to have grade 4 thrombocytopenia. Peripheral blood gene expression of the BCL2 family of apoptotic markers (BCL2L1 and BAX transcripts) was significantly associated with grade 4 hematologic toxicity. RNA sequencing demonstrated little overlap in the top modulated peripheral blood transcripts between randomized arms. Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after I-131-MIBG and concomitant radiation sensitizers affect extent of modulation. Biomarkers related to hematopoietic damage and apoptosis were associated with hematologic toxicity. (C) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study evaluated the efficacy of I-131-MIBG in combination with different radiation sensitizers on patients with relapsed neuroblastoma. The results showed significant modulation of radiation-associated biomarkers after I-131-MIBG treatment, and the extent of modulation was affected by concomitant radiation sensitizers. Blood biomarkers were associated with treatment response and toxicity.